Abnormal deposition of .beta.-amyloid in the cells and tissues of a human patient is a prominent feature associated with several brain disorders in humans. These disorders include Alzheimer's disease, Alzheimer disease changes associated with Down's syndrome, hereditary cerebral hemorrhage with amyloidosis of Dutch origin (HCHWA-D), Parkinson-dementia of Guam, sporadic cerebral amyloid angiopathy (SCAA) and dementia pugilistica. Abnormal accumulation of .beta.-amyloid is also implicated in severe and progressive muscle diseases such as sporadic inclusion body myositis (IBM) and hereditary inclusion body myopathy (hIBM). Collectively, these diseases are referred to as .beta.-amyloidoses.
Alzheimer's disease is the most common cause of dementia in aging humans in many developed countries. The disease is characterized by gradual loss of memory, emotional stability and judgment. Death usually occurs between four and twelve years after the onset of symptoms. Patients with Alzheimer's disease require constant supervision and eventual total custodial care due to their severely debilitated condition. The cost of diagnosing and managing Alzheimer's patients is currently estimated at more than $80 billion a year in the U.S. alone [Selkoe, D. J. (1991) Scientific American 265:68-78].
Two types of brain lesions, senile plaques and neurofibrillary tangles, were originally described by Dr. Alois Alzheimer in patients with dementia. In Alzheimer's disease patients, senile plaques occur in great numbers in the areas of the brain responsible for cognitive function, particularly the cerebral cortex, hippocampus and amygdala. These spherical plaques consist of altered neurites (axons and dendrites), which are the long tapering portions of neurons, surrounding an extracellular mass of filaments. It is presently believed that degeneration of neurons in Alzheimer's disease patients is the result of their entanglement in this filament matrix. There is currently no treatment for the prevention or retardation of the progression of Alzheimer's disease.
At approximately 40-50 years of age, individuals with Down's syndrome acquire brain lesions which are characteristic of Alzheimer's disease. The behavior as well as the mental ability of these patients begins to deteriorate at about the same time. The cerebrovascular plaques which are observed in Down's syndrome patients over forty years of age are known to comprise .beta.-amyloid. Also, recent studies suggest that women under age 35 who have borne a child with Down's syndrome are themselves more likely to develop Alzheimer's disease earlier in life than women who bear children with Down's syndrome at or above age 35.
Hereditary cerebral hemorrhage with amyloidosis of Dutch type (HCHWA-D) is an autosomal dominant disease characterized by extensive .beta.-amyloid plaques in the cerebral cortex. The senile plaques are widespread and have a fibrillar appearance. Also, amyloid fibrils are known to infiltrate small arteries, arterioles and veins in these individuals. Patients with HCHWA-D suffer recurrent intracerebral hemorrhages leading to early death at the age of 50 to 60 years old. In almost 50% of the patients the first cerebral hemorrhage leads to death.
Parkinson-dementia of Guam is caused by extensive deposition of .beta.-amyloid in the brain, and is characterized by parkinsonism and slowly progressive dementia. This disease also exhibits the formation of neurofibrillary tangles similar to those observed in Alzheimer's disease patients.
Sporadic cerebral amyloid angiopathy (SCAA) is characterized by an intense and extensive .beta.-amyloid deposition within cerebral arteries, veins, arterioles and capillaries. SCAA is observed in 50% of the autopsies performed on individuals over 50 years of age. Symptoms include dementia, cerebral hemorrhages and ischemic strokes.
Severe head injury in humans may lead to a chronic degenerative condition referred to as dementia pugilistica. This disorder is a consequence of abnormal deposition of .beta.-amyloid in the form of diffuse plaques in the neurons and neurites of the patient's brain, and is characterized by a cavum septum, neuronal loss, cerebellar scarring and intense neurofibrillary tangle formation in the cortex.
Muscle diseases such as sporadic inclusion body myositis (IBM) and hereditary inclusion body myopathy (hIBM) are characterized by abnormal accumulation of .beta.-amyloid in vacuolated muscle fibers, and are most common in patients of who are fifty-five years of age or older. This is a progressive disease resulting in severe disability, whose symptoms include proximal and distal muscle weakness, thinning of the forearms, male predominance and either the absence of or a poor response to immunosuppressive treatment.
There is a long felt need for effective diagnosis, prophylaxis and treatment of these and other conditions whose common feature includes abnormal .beta.-amyloid synthesis and accumulation.